This continuing medical education activity is supportedthrough an unrestricted educational grant from Eyetech Inc.

AMD, DME, and RVO

Current and Emerging Considerationsin the Management of

CME MONOGRAPH

Original Release: September 28, 2011Last Review: September 19, 2011Expiration: September 30, 2012

FacultyVictor H. Gonzalez, MDFounderValley Retina InstituteMcAllen, TexasClinical FacultyDepartment of Human GeneticsUniversity of Texas–HoustonHouston, Texas

John A. Wells III, MDFounderPalmetto Retina CenterColumbia, South Carolina

Program ChairmanScott W. Cousins, MDRobert Machemer Professor ofOphthalmology and Immunology

Vice Chair for Research DirectorDuke Center for Macular DiseasesDuke Eye CenterDuke University School of MedicineDurham, North Carolina

Sponsored by The New York Eye and Ear Infirmary

In joint sponsorship with MedEdicus LLC

Highlights from a CME symposium heldApril 30, 2011, in Fort Lauderdale, Florida

Are We Undertreating Neovascular AMD?

Scott W. Cousins, MD

Consider a patient with age-related macular degeneration (AMD) and classic choroidal neovas-cularization (CNV) with 20/100 vision. He receives 3 doses of an anti-vascular endothelialgrowth factor (VEGF) agent and has a very favorable response with good visual acuity, no leak-age of fluid on fluorescein angiography (FA), and no fluid on optical coherence tomography(OCT). Now what do you do? After the initial induction, how many anti-VEGF treatments peryear, on average, are required to maintain good vision?

The ranibizumab registry trials (MARINA1 and ANCHOR2) evaluated monthly injections through2 years of therapy; the drug is labeled for indefinite monthly injections. Is it possible to achievesimilar outcomes with less frequent dosing? There are at least 4 popular regimens.

Option 1: Ranibizumab induction with quarterly retreatmentTwo published studies, PIER3 and EXCITE,4 have evaluated the regimen of 3 monthly inductiondoses of ranibizumab followed by scheduled quarterly retreatments. In comparison to the out-comes of the ANCHOR trial, the PIER protocol was associated with significant loss of visual acu-ity during the maintenance phase. Similarly in the EXCITE study, quarterly injections wereassociated with substantially smaller gains of visual acuity than the monthly therapy providedin ANCHOR and MARINA. These studies demonstrate that induction with 3 monthly injectionsfollowed by quarterly maintenance is inadequate for gaining and maintaining visual acuity.

Option 2: Ranibizumab induction with variable retreatmentAt least 6 studies have evaluated the regimen of initial monthly induction dosing followed byvariable dosing based on clinical criteria: PrONTO,5 SAILOR,6 SUSTAIN,7 CATT,8 HORIZON,9 anda study from the Cleveland Clinic.10

PrONTO included 40 patients who received 3 doses of ranibizumab and then were followed ona monthly basis with examination, visual acuity, and OCT, with retreatment based on specificindications. By following this rigorous protocol, patients maintained their initial good visualacuity gains for up to 2 years.

The recent CATT study was a head-to-head comparative efficacy study that evaluated monthlyranibizumab versus monthly bevacizumab versus PRN ranibizumab and PRN bevacizumab (Figure 1).Monthly ranibizumab and monthly bevacizumab were each associated with similar excellent results.In the PRN groups, the 2 drugs were comparable, but, while not statistically significant, there wasa trend toward a slight decrease in visual acuity compared with that achieved with monthly dosingfor both drugs. Importantly, the PRN groups received an average of 7 injections for ranibizumab and8 injections for bevacizumab in the first 12 months, compared with the 12 injections in the monthlygroups, to maintain good vision.A substantial proportion of patients in all treatment groups showedevidence of persistent leakage on fluorescein and OCT testing at 12 months.

The remaining 4 studies relied on less rigorous follow-up or less rigorous retreatment criteria,resulting in less impressive visual acuity results. Collectively, these studies demonstrate thateven with aggressive treatment, neovascular AMD remains active for years. CATT and PrONTOstudies indicate that “as needed” treatment protocol associated with rigorous monthly follow-upcan preserve vision gains for 2 years. Studies such as SAILOR, HORIZON, and others, using lessrigorous follow-up protocols, resulted in vision drop-off.

Figure 1. Visual acuity outcomes in CATT.8 ©Massachusetts Medical Society. Reprinted with permission.

Learning Method and MediumThis educational activity consists of a supplement and ten (10) study questions. The participant should, in order, readthe learning objectives contained at the beginning of this supplement, read the supplement, answer all questions inthe post test, and complete the evaluation form. To receive credit for this activity, please follow the instructions providedon the post test and evaluation form. This educational activity should take a maximum of 1.0 hour to complete.

Content SourceThis continuing medical education (CME) activity captures content from an interactive, case-based CME symposiumheld April 30, 2011, in Fort Lauderdale, Florida.

Activity DescriptionThis monograph discusses highlights from a CME Symposium held April 30, 2011. It will describe new research andincorporate expert guidance for individualizing anti-vascular endothelial growth factor (VEGF) therapy for patientswith age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusions (RVOs).

Learning ObjectivesAfter successfully completing this activity, you will have improved your ability to:

• Discuss alternate treatment protocols for patients with AMD in whom long-term anti-VEGF therapyposes a safety concern

• Review the current and emerging treatment options for DME and RVO• Choose optimal dosing strategies from the available therapies for patients with AMD, DME, or RVO

Target AudienceThis educational activity is intended for retina specialists.

Accreditation StatementThis activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accred-itation Council for Continuing Medical Education through the joint sponsorship of The NewYork Eye and Ear Infirmaryand MedEdicus LLC. The New York Eye and Ear Infirmary is accredited by the ACCME to provide continuing medicaleducation for physicians.

AMA Credit Designation StatementThe New York Eye and Ear Infirmary designates this enduring material for a maximum of 1.0 AMA PRA Category 1Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Grantor StatementThis continuing medical education activity is supported through an unrestricted educational grant from Eyetech Inc.

Mission StatementIt is The New York Eye and Ear Infirmary Institute for Continuing Medical Education’s stated mission to create med-ical education activities that will serve to increase the knowledge, skills, professional performance, and relationshipsthat a physician uses to provide services for patients, the public, or the chosen profession.

Disclosure Policy StatementIt is the policy of The New York Eye and Ear Infirmary that the faculty and anyone in a position to control activity con-tent disclose any real or apparent conflicts of interest relating to the topics of this educational activity, and also dis-close discussions of unlabeled/unapproved uses of drugs or devices during their presentation(s). The New York Eyeand Ear Infirmary has established policies in place that will identify and resolve all conflicts of interest prior to thiseducational activity. Full disclosures of faculty/planner and their commercial relationships, if any, follow.

DisclosuresScott W. Cousins, MD, has had a financial agreement or affiliation during the past year with the following commercialinterests in the form of Consultant/Advisory Board: Alcon, Inc; Allergan, Inc; Apeliotus Vision Science; Eyetech Inc;Fovea Pharmaceuticals; Genentech, Inc; Heidelberg Engineering; Novartis; Ophthotech; Pfizer Inc; QLT Inc; andViroPharma Incorporated; Contracted Research: Alcon, Inc; and iCo Therapeutics Inc.

Victor H. Gonzalez, MD, has had a financial agreement or affiliation during the past year with the following com-mercial interests in the form of Honoraria: Eyetech Inc; ISTA Pharmaceuticals, Inc; and Pfizer Inc; Consultant/AdvisoryBoard: Eyetech Inc; Genentech, Inc; ISTA Pharmaceuticals, Inc; and Pfizer Inc; Contracted Research: Alcon, Inc;Alimera Sciences; Genentech, Inc; Iconic Therapeutics, Inc; ISTA Pharmaceuticals, Inc; Ophthotech; Pfizer Inc; Regen-eron Pharmaceuticals, Inc; Steba Biotech Ltd; and ThromboGenics NV.

John A.Wells III, MD, has had a financial agreement or affiliation during the past year with the following commercialinterests in the form of Consultant/Advisory Board: Allergan, Inc; and Eyetech Inc; Contracted Research: Alcon, Inc;Eyetech Inc; Genentech, Inc; Iconic Therapeutics, Inc; Ophthotech; Regeneron Pharmaceuticals, Inc; and StebaBiotech Ltd.

Editorial Support DisclosuresTony Realini, MD, MPH; Cynthia Tornallyay, RD, MBA, CCMEP; Kimberly Corbin, CCMEP; and Barbara Lyon haveno relevant commercial relationships to disclose.

Disclosure AttestationEach of the contributing physicians listed above has attested to the following: 1) that the relationships/affiliationsnoted will not bias or otherwise influence his/her involvement in this activity; 2) that practice recommendationsgiven relevant to the companies with whom he/she has relationships/affiliations will be supported by the best avail-able evidence or, absent evidence, will be consistent with generally accepted medical practice; and 3) that all rea-sonable clinical alternatives will be discussed when making practice recommendations.

Off-Label DiscussionThis activity includes off-label discussion of bevacizumab for AMD, DME, and RVO; pegaptanib for DME and RVO;ranibizumab for DME.

To Obtain AMA PRA Category 1 Credit™To obtain AMA PRA Category 1 Credit™ for this activity, read the material in its entirety and consult referencedsources as necessary. Complete the evaluation form along with the post test answer box within this supplement.Remove the Activity Evaluation page from the printed supplement or print the Activity Evaluation page from theDigital Edition. Return via mail or fax to Kim Corbin, Director, ICME, The New York Eye and Ear Infirmary, 310 East14th Street, New York, NY 10003 or fax to (212) 353-5703. Your certificate will be mailed to the address that youprovide on the evaluation form. Please allow 3 weeks for mailed/faxed forms to process. Note: You must score a 70%or higher to receive credit for this activity.

DISCLAIMERThe views and opinions expressed in this educational activity are those of the faculty and do not necessarily representthe views of The New York Eye and Ear Infirmary, MedEdicus LLC, or Eyetech Inc. Please refer to the official pre-scribing information for each product for discussion of approved indications, contraindications, and warnings.

This CME activity is copyrighted to MedEdicus LLC ©2011. All rights reserved.

2

AMD, DME, and RVO

Current and Emerging Considerationsin the Management of

Mean Number of Injections

Ranibizumab monthly 11.7Bevacizumab monthly 11.9Ranibizumab as needed 6.9Bevacizumab as needed 7.7

3

Option 3: Ranibizumab induction followed by pegaptanib maintenanceRanibizumab inhibits all VEGF isoforms while pegaptanib selectively inhibits VEGF165. While the2 drugs have never been compared in a head-to-head trial, cross-trial comparison suggeststhat chronic pan-VEGF inhibition is superior to selective VEGF165 inhibition.11 In an effort to min-imize adverse events associated with pan-VEGF inhibition, might a regimen of ranibizumab orbevacizumab induction followed by pegaptanib maintenance be effective? The recent LEVELstudy addressed this question.12 In the study, 36% of the patients were induced with beva-cizumab, 42% were induced with ranibizumab, and 19% received multiple agents. After theinitial improvement in vision, maintenance with pegaptanib, a VEGF165-selective agent, over thenext year showed stable maintenance of visual acuity. There was no difference if patients wereinduced with bevacizumab or with ranibizumab, and the OCT thickening did not change duringthe course of the year. The patients did not develop recurrent leakage (Figure 2).

Option 4: Treat and extendThe “treat-and-extend” regimen consists of induction therapy followed by gradually increasingthe interval between treatments based on clinical status. There are only a few observationalstudies suggesting that this approach may have some benefit.13,14 These studies showed thatthe treat-and-extend approach can produce long-term stable vision. In both studies, patientsrequired, on average, 7 to 8 injections during the course of the year to maintain visual gains.

Current Practice PatternsSince frequent, scheduled injections are the only proven approach to maintaining initial visiongains, and patients generally need 7 to 8 injections during the course of a year, how closelydo current practice patterns in the United States adhere to this regimen?

Our group conducted a Medicare claims analysis to identify the average number of injectionsreceived during each of the first 2 years following a new diagnosis of neovascular AMD.15 Inthe first 12 months, patients received an average of 4 injections; during the second 12 months,the number dropped to an average of only 2 injections. Only 21% of patients who were treatedwith ranibizumab and 10% of patients treated with bevacizumab received more than 6 injec-tions. In contrast, recall that patients in the PRN arms of CATT received 7 to 8 injections, onaverage. The duration of therapy was also surprising. Fifty percent of patients received onlyinduction and no maintenance injections, and 80% of patients received no further injectionsat all after the first 18 months. The bottom line is this: Patients with neovascular AMD arebeing undertreated in the real world.

Should Safety Issues Guide VEGF InhibitionTreatment Choices?

Scott W. Cousins, MD

Consider a patient with neovascular AMD, an occult CNV lesion, visual acuity of 20/60, with OCT evi-dence of retinal fluid and outer retinal disruption. Chronic pan-VEGF inhibition seems like a reason-able therapy. But suppose the patient suffered a stroke 1 month ago. Should this health issue changeour management? To address this important issue, we will consider 6 true/false questions.

Question 1. True or False? The United States and the European Union havea robust process for monitoring postmarketing safety.False. The postmarketing safety surveillance system is the medical community reportingadverse events to the US Food and Drug Administration (FDA) MedWatch system. This processrequires that we clinicians fill out a form, then submit it, either by e-mail or fax, to the FDA everytime we suspect that a patient suffered an adverse event that may or may not be caused bya drug. How many readers of this monograph have ever reported a safety issue to MedWatch?I suspect very few. That is why our postmarketing safety surveillance system is not effective.It is not part of our culture to report adverse events in organ systems for which we are not pri-marily responsible.

Question 2. True or False? Most important drug toxicities are identifiedduring phase 3 pivotal trials.False. Phase 3 trials are typically powered to detect a 1% incidence of catastrophic adverseevents. This is very different from being powered to detect a 1% increase in incidence com-pared with a control group or a baseline rate, a value that would be more useful. The populationfrom which we draw study patients for AMD trials is the elderly population, and those patientsoften have background health issues such as atherothrombotic events, stroke or heart attacks,systemic hypertension, and any kind of systemic hemorrhage, such as gastrointestinal orurinary. Phase 3 trials are generally not powered to detect small but clinically significantdifferences in adverse event rates from baseline or between groups.

What do we know about safety from the key phase 3 trials? In the VEGF165-selective pegaptanibtrial, there was no increase in adverse events seen in the pegaptanib groups over those seen inthe sham group, even at the highest dose, which was 10-fold greater than the approved dose.11

In the MARINA ranibizumab trial, there was a 50% increase in the incidence of stroke in the patientswho received the pan-VEGF inhibitor rather than sham.1 In the SAILOR trial, which was the exten-sion trial following MARINA and ANCHOR, patients were randomized to either 0.5 mg or 0.3 mg ofranibizumab.6 The larger-dose group showed a slight increase in stroke rate compared with thelower-dose group, though not statistically significant. Notably, however, the patients who had a priorstroke suffered an almost 10% rate of second stroke if they received the higher dose that is cur-rently commercially available. A meta-analysis of the MARINA, ANCHOR, and FOCUS studiesdemonstrated that treated patients experienced almost a 3-fold increased rate of strokes comparedwith control patients.16 In the RISE study of ranibizumab for diabetic macular edema (DME), therewas a trend toward increased rate of stroke and death in patients receiving the higher doses ofranibizumab.17 Finally, in the CATT study, there was a doubling of the rate of death from any causein the PRN bevacizumab group compared with the other groups, and an increased rate of serioussystemic events that required hospitalization, also in the bevacizumab group.8

In summary, the clinical trial data suggest safety signals regarding the risk of stroke in patientsreceiving ranibizumab and, perhaps, bevacizumab, but the phase 3 trials are not designed togive us absolute confirmation of safety. Postmarketing surveillance is necessary to fully char-acterize the safety profiles of drugs.

Question 3. True or False? Drugs administered intravitreally do not enterthe systemic circulation and pose no systemic safety risks.False. Virtually every drug that we inject into the eye can and does reach the systemic circu-lation. From a safety perspective, the issue is not whether the drug reaches the systemic cir-culation, but rather how long that drug persists within the systemic circulation. Pegaptaniband ranibizumab are smaller molecules and have very short half-lives, but bevacizumab is afull-length antibody and has a longer half-life. Our data demonstrate that bevacizumab can lastin the blood for as long as 6 weeks post-injection (unpublished).

Question 4. True of False? The small amount of systemically absorbed anti-VEGF medication is inadequate to significantly inhibit systemic VEGF levels.False. VEGF is present in blood, where it serves an important role in regulating blood pressure,promoting vascular repair, stimulating collateral vessel formation and other physiological func-tions. Most blood VEGF resides in platelets, which are essentially little bags of growth factorsand clotting factors that are released from the bone marrow. This VEGF, when released fromplatelets in the setting of vascular injury, induces vascular repair and dilation around the throm-bus and also induces collateral formation. So, systemic VEGF is critical to maintaining healthyblood vessels. The average patient’s serum VEGF level, after clot-induced release of plateletVEGF, is approximately 380 pg/mL, but there is a surprisingly large range of values from almostundetectable to more than 1000 pg/mL (Figure 3). It has been demonstrated recently that intra-vitreal anti-VEGF therapy lowers systemic VEGF levels for as long as a month after an injection.16

Perhaps those patients with low systemic VEGF levels are most susceptible to systemic VEGFblockade because they don’t have adequate reserves of systemic VEGF to maintain cerebral vas-cular integrity, and are therefore more at risk for stroke when receiving anti-VEGF therapy.

Figure 2. Mean visual acuity changes in the LEVEL study.12 Reprinted with permission.

Figure 3. The range ofserum VEGF levels in patientswith neovascular AMD.

Scott W. Cousins, MD,unpublished.

10%–50% is VEGF 121

4

DME CaseVictor H. Gonzalez, MD

A 72-year-old woman with a 9-year history of diabetes and systemic hyperten-sion presents with persistent DME in the right eye and a Snellen visual acuity of20/60. The patient had clinically significant macular edema despite previousfocal laser. The FA demonstrated an enlarged foveal avascular zone and leakagefrom microaneurysms. The OCT demonstrated retinal edema with intraretinalcysts involving the central macula.

I elected to treat this patient with pegaptanib. The decision was based on phase3 data that supports the use of this medication in DME,20 and the fact that I didnot want to apply further laser treatment to the microaneuryms that were leak-ing because of the fear of making the macular ischemia worse.

My approach in these eyes is to start with an induction phase of 2 to 4 injec-tions of an anti-VEGF agent. If there is inadequate response, I will consideradding laser at that time.

The patient underwent a series of injections with pegaptanib every 6 weeks.After 4 injections and no laser, there was significant improvement in her clinicalappearance in the right eye, with a commensurate improvement in visual acuityin the right eye to 20/40. The course of the right eye is illustrated in Figure 4.

Figure 4. The effects of anti-VEGF therapy (no laser) on macular edema associated with DME.A. change in clinical fundus appearance; B. change in FA (early and late phase); C. change in OCT.

Photo Courtesy Victor H. Gonzalez, MD

A.

B.

C.

Question 5. True or False? All patients with AMD are at equal risk forsystemic complications of intravitreal anti-VEGF therapy.False. Our recent Medicare analysis demonstrated no increased systemic safety concernsacross the entire AMD Medicare population when considered as a group.15 However, prelimi-nary analyses of high-risk subgroups suggest that a different picture may emerge. Patients withdiabetes exhibited a 30% increase in stroke rate with bevacizumab over that with photody-namic therapy (PDT). Patients with peripheral artery disease, a significant risk factor for stroke,had a 2-fold higher stroke risk after bevacizumab therapy than after PDT. These results needto be confirmed by analysis of additional cohorts of subjects.

There might be a subset of patients at higher risk of stroke following anti-VEGF therapy forAMD. The profile of this subset is still being characterized, but for now, it appears to be peoplewith a recent stroke history, perhaps those with diabetes, and perhaps patients with low sys-temic VEGF levels.

Question 6. True or False? If intravitreal anti-VEGF therapy causessystemic safety events, we should be seeing many more strokes orother complications in our practices.False. A low frequency of events may not be obvious to any single practitioner, but still couldbe significant to the population overall. Consider an example. Let us say there is a 2% annualstroke rate among patients in the AMD age range, and that anti-VEGF therapy causes a 50%increase in stroke rate. If there are 150,000 AMD patients undergoing new therapy each year,we would expect approximately 3000 baseline strokes due to underlying vascular illness and1500 additional drug-related strokes per year. Given that there are approximately 1500 retinaspecialists in the United States, each would see, on average, only 1 additional stroke per yearand would likely not notice this or attribute it to drug therapy. This 50% increased risk wouldnot be obvious to any single practitioner, but it would be hugely important as a public health risk.

Diabetic Macular Edema: Examining the ClinicalEvidence and Applying It to Practice

Victor H. Gonzalez, MD

Laser photocoagulation has remained the standard therapy for DME for years. Recently, anumber of major clinical trials have evaluated novel therapies for DME.

The DRCRnet study compared ranibizumab with immediate or delayed laser to triamcinoloneplus laser or laser alone.18 Four monthly injections were followed by a PRN monthly retreatmentschedule; following initial laser (prompt or deferred), PRN retreatment up to every 4 monthswas permitted. The group of individuals who received ranibizumab with either prompt ordelayed laser had a significantly better visual acuity outcome compared with those whoreceived laser treatment alone, and triamcinolone was of no additional benefit when combinedwith laser. Although ETDRS and other trials have demonstrated that laser photocoagulation isclearly superior to observation, the DRCRnet study suggests that pharmacologic treatmentwith ranibizumab is superior to laser alone. The role for combination approaches with laser andpharmacologic therapy remains to be determined.

The DRCRnet study raised an important question: How effective is ranibizumab alone withoutlaser? This important question was answered by the RESTORE study.19 In RESTORE, whichwas a multicenter, randomized, double-masked trial conducted in Europe, patients with DMEwere assigned to therapy with ranibizumab alone, laser alone, or the combination ofranibizumab plus laser. Injections were given monthly, for 3 injections, then PRN. The 2 groupsreceiving ranibizumab fared significantly better than the laser-only group, and there was no dif-ference in the ranibizumab group versus the ranibizumab-plus-laser group. The RISE and RIDEstudies, of similar design, confirmed these findings.17 No increase in cardiovascular or cere-brovascular adverse events was noted in the ranibizumab groups in the RESTORE study.

Pegaptanib has also been evaluated in a multicenter, randomized, double-masked phase 3DME trial in Europe.20 Patients with DME received either pegaptanib or sham injections every6 weeks, and could also receive laser after week 18 and up to every 17 weeks thereafter.Unlike the DRCRnet study, in which retreatment was determined by a reading center based onFA and OCT results, the pegaptanib study permitted the investigators to determine the needfor retreatment. This is more real-world in its approach. At the 52-week primary end point, out-comes were significantly better in the pegaptanib group compared with the sham group. Fur-ther, significantly fewer patients treated with pegaptanib required laser therapy. Importantly,there were no safety signals in the pegaptanib group compared with the sham group.

The DME treatment paradigm is evolving, driven by the aforementioned and ongoing studiesexploring the role of novel therapies in this common disease process. Important questionsremain unanswered. How should we select the right drug for each patient? How long must wecontinue anti-VEGF therapy to maintain control of DME? Further study and more head-to-headtrials are needed to clarify the optimal drugs and dosing regimens for DME. (see Sidebar)

5

RVO CasesJohn A. Wells III, MD

Case 1An 83-year-old man presents for routine examination and is found to have a mild, nonischemic CRVO in the righteye, with 20/30 vision and mild macular edema. Past history includes chronic systemic hypertension and a CRVO inhis left eye 20 years ago that resolved spontaneously.

I elected to observe his right eye because the natural history of macular edema in nonischemic CRVO suggests thatapproximately 30% of cases resolve without treatment.27 Two weeks later, however, he returned and his vision haddropped to counting fingers and he had significant macular edema. It is unknown whether treating him 2 weeksearlier would have prevented this from happening.

We discussed therapeutic options and he was reluctant to undergo monthly anti-VEGF injections. We gave anintravitreal triamcinolone 2 mg/0.05 cc injection and after 27 days, his edema was better, though not resolved, andhis vision was marginally better, at 20/400.

Three months after the initial injection (during which time he had begun taking warfarin), macular edema persisted,but there was new rubeosis. At this point, I administered bevacizumab 1.25 mg and performed panretinal photoco-agulation (PRP). He missed his next appointment and returned in 7 weeks’ time with massive edema but no rubeo-sis. Despite a second bevacizumab injection, severe macular edema persisted and rubeosis recurred; anotherbevacizumab injection and more PRP was given. Regrettably, at this visit he also had an asymptomatic CRVO in theleft eye with no macular edema. He and I discussed treatment in the left eye and elected to observe initially.

Four weeks later he had minimal edema in the left eye and his vision was 20/40. No treatment was given. The righteye was stable with poor vision and mild macular edema but no rubeosis or glaucoma.

A few weeks later, he presented with significant macular edema in both eyes and vision of counting fingers with theright eye and 20/300 with the left eye. Because the vision potential in the right eye was poor, we elected for treat-ment in the left eye only. He subsequently received a series of 8 bevacizumab injections in that eye over 9 months.At last follow-up, left eye vision was 20/60, with no macular edema clinically or on OCT, and no rubeosis in that eye.

Considerations relating to this case include whether or not initiating treatment earlier, before the severe macularedema and the vision loss, would have resulted in a better visual outcome and, as suggested by the CRUISE,SCORE, and dexamethasone intravitreal implant trial results, that anti-VEGF therapy gives better vision outcomesand reduces the risk of rubeosis compared with steroids. Also, chronic therapy may be required to maintain visiongains and resolution of macular edema.28

Case 2A 70-year-old man in excellent health, except that he is a former smoker, presents with a BRVO (Figure 5). His pre-senting acuity is 20/60 and he has significant edema and hemorrhage. In deciding whether or not to treat him, it isworth noting that the natural history of BRVO suggests that approximately 18% to 41% of eyes with BRVO andmacular edema resolve without treatment, but it is uncommon for untreated eyes to achieve better than 20/40vision.29 Conversely, the potential advantages of early treatment include prevention of macular tissue damage fromchronic edema, more rapid resolution of hemorrhage, faster visual improvement, and prevention of neovasculariza-tion. In BRAVO, eyes with shorter durations of edema had better vision after treatment and eyes receivingranibizumab after 6 months of sham injections had less vision improvement than eyes treated from baseline.

I recommended treatment, but the patient elected observation and returned in 6 weeks with worse vision and soelected treatment at that time. After 2 bevacizumab injections, his vision improved to 20/30 and there was lesshemorrhage and reduced edema. After 5 injections, he had persistent edema, though much less than before. At thispoint, I performed grid laser. Six weeks later, his visual acuity was 20/40, but he had worsening edema. After a fewmore injections, I arranged to see him 2 weeks after the last injection. At 2 weeks post-injection, he was nearlyfluid-free. The lesson here is that RVO may be associated with a high VEGF load: injections more frequently thanevery 4 weeks may be necessary. Also, in this case of BRVO, the addition of grid laser treatment did not seem toreduce the need for continued anti-VEGF therapy to control macular edema and maintain vision. Similarly, in theDRCRnet trial comparing ranibizumab and deferred laser to ranibizumab plus prompt laser for diabetic macularedema, the addition of laser to anti-VEGF therapy did not appear to significantly alter the number of anti-VEGFtreatments given over the first year.30 This case, and many others in my personal clinical experience, suggests asimilar phenomenon may be found in treating macular edema due to BRVO.

Figure 5. Classic BRVO. Left, red-free fundus photograph; Right, FA.

Photo Courtesy John A.Wells III, MD

ANCHOR=Anti-VEGF Antibody for the Treatment of Predominantly ClassicChoroidal Neovascularization in Age-Related Macular Degeneration

BRAVO=Study of the Efficacy and Safety of Ranibizumab Injection in PatientsWith Macular Edema Secondary to Branch Retinal Vein Occlusion

CATT=Comparison of AMD Treatment Trials

CRUISE=Study of the Efficacy and Safety of Ranibizumab Injection in PatientsWith Macular Edema Secondary to Central Retinal Vein Occlusion

DRCRnet=Diabetic Retinopathy Clinical Research Network

ETDRS=Early Treatment Diabetic Retinopathy Study

EXCITE=Efficacy and Safety of Ranibizumab in Patients With SubfovealChoroidal Neovascularization Secondary to Age-Related Macular Degeneration

HORIZON=Extension Study to Evaluate the Safety and Tolerability ofRanibizumab in Subjects With Choroidal Neovascularization Secondary toAMD or Macular Edema Secondary to RVO

LEVEL=Evaluation of Efficacy and Safety in Maintaining Visual Acuity withSequential Treatment of Neovascular AMD

MARINA=Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumabin the Treatment of Neovascular Age-Related Macular Degeneration

PIER=Randomised, Double-Masked, Sham-Controlled, 2-Year StudyDesigned to Assess the Safety and Efficacy of Ranibizumab in Patients WithNeovascular (Wet) Age-Related Macular Degeneration (With or WithoutChoroidal Neovascularisation)

PrONTO=Prospective Optical Coherence Tomography Imaging of PatientsWith Neovascular AMD Treated With Intra-Ocular Ranibizumab

RESTORE=Ranibizumab Monotherapy or Combined With Laser Versus LaserMonotherapy for Diabetic Macular Edema

RIDE=Study of Ranibizumab Injection in Subjects With Clinically SignificantMacular Edema With Center Involvement Secondary to Diabetes Mellitus

RISE=Study of Ranibizumab Injection in Subjects With Clinically SignificantMacular Edema With Center Involvement Secondary to Diabetes Mellitus

SAILOR=Safety Assessment of Intravitreal Lucentis® for Age-RelatedMacular Degeneration

SCORE=Standard Care vs Corticosteroid for Retinal Vein Occlusion

SUSTAIN=Study of Ranibizumab in Patients With Subfoveal ChoroidalNeovascularization Secondary to Age-Related Macular Degeneration

Retinal Vein Occlusion:Applying Clinical Evidence

to Practice

John A. Wells III, MD

In the past few years, our therapeutic options for macularedema associated with retinal vein occlusion (RVO) haveexpanded substantially. The recent SCORE study demon-strated that intravitreal triamcinolone was superior to obser-vation in eyes with macular edema due to central retinal veinocclusion (CRVO), but no better than grid laser photocoagula-tion in eyes with macular edema due to branch retinalvein occlusion (BRVO).21,22 The dexamethasone intravitrealinjectable implant demonstrated efficacy against macularedema due to RVO for as long as 30 to 60 days at a time, andwas approved by the FDA for this indication in 2009.23

Pegaptanib for CRVO was the first published study to demon-strate a benefit to vision with anti-VEGF therapy in CRVO.24

More recently, the BRAVO and CRUISE studies demonstratedthat intravitreal ranibizumab, given as 6 monthly injectionsfollowed by PRN retreatment for an additional 6 months, washighly effective in improving visual acuity.25,26 In 2010, the FDAexpanded the ranibizumab label to include macular edemaassociated with BRVO and CRVO.

Despite the lessons learned from these important trials, thereremain several unanswered questions. When should we initiatetreatment? What is the optimal drug? What is the optimal dos-ing interval? How long should we continue treatment? Is therea role for combination therapy with laser and anti-VEGF drugs?

Steroids have some advantages over VEGF inhibitors. They areless expensive and can be administered less frequently. Butthey also have disadvantages, which are generally related tosafety, including cataract, glaucoma, and higher rates of neo-vascularization. For these reasons, I prefer anti-VEGF therapyto steroid therapy in eyes with macular edema due to RVO.

Clinical therapeutic approaches to patients with RVO arediscussed in the cases. (see Sidebar)

To obtain AMA PRA Category 1 Credit™ for this activity, you must complete the CME PostTest by writing the best answer to each question in the Answer Box located on the ActivityEvaluation/Credit Request form on the following page.

1. According to the preponderance of evidence, which of the following is true regardinganti-VEGF therapy for neovascular AMD?

a. Monthly therapy provides the best resultsb. PRN therapy is as effective as monthly therapyc. A regimen of monthly therapy for several months followed by PRN injections is as

effective as monthly therapy

2. Which of the following is false regarding treatment patterns for neovascular AMD in theUnited States?

a. Most patients are undertreatedb. Most patients receive 8 to 10 injections per yearc. Most patients receive no further injections after the first 18 months of therapy

3. Which of the following is true regarding postmarketing drug safety assessment in theUnited States?

a. There is a robust system in place to track adverse eventsb. All important safety issues are identified in phase 3 trialsc. It is each physician’s responsibility to report drug-related adverse events to the FDA

4. Which of the following is false regarding systemic VEGF levels?a. Systemic VEGF levels do not vary substantially between individualsb. Blood VEGF is stored in plateletsc. VEGF is important for the repair of damaged blood vessels

5. Which of the following is true regarding systemic exposure to intravitreally administeredanti-VEGF therapy?

a. No anti-VEGF therapies escape the eye to reach the systemic circulationb. Systemic levels of anti-VEGF therapies injected into the eye pose equal risk to all

patients with neovascular AMDc. Stroke may be a risk of systemic exposure of pan-VEGF-suppressing therapies

6. Which of the following is true regarding DME?a. Laser therapy has been the gold standard therapy for many yearsb. Triamcinolone has recently been shown to be the best therapy for DMEc. Anti-VEGF therapy is ineffective in treating DME

7. Which of the following is false regarding anti-VEGF therapy for DME?a. Selective VEGF165 inhibition is an effective therapy for DMEb. Duration of treatment remains unclearc. Anti-VEGF therapy plus laser is more effective than anti-VEGF therapy alone

8. Which of the following is true regarding the SCORE study for retinal vein occlusions?a. Triamcinolone was more effective than laser for BRVOb. Triamcinolone was more effective than observation for CRVOc. Both a. and b.

9. For what period of time is the dexamethasone intravitreal implant effective againstmacular edema associated with retinal vein occlusion?

a. 2 to 3 weeksb. 30 to 60 daysc. 6 to 9 months

10. Which of the following is true regarding steroids versus anti-VEGF therapy for retinalvein occlusions?

a. Steroids are more likely than anti-VEGF therapy to cause cataractsb. Anti-VEGF agents are more likely than steroids to cause glaucomac. Neovascularization is more common in eyes treated with anti-VEGF therapy

6

AMD, DME, and RVO

Current and Emerging Considerationsin the Management of

CME Post Test

References 1. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab forneovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.2.Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin forneovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.3. Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumabfor neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol.2010;150(3):315-324.e1. 4. Schmidt-Erfurth U, Eldem B, Guymer R, et al; EXCITE Study Group.Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-relatedmacular degeneration: The EXCITE Study. Ophthalmology. 2011;118(5):831-839. 5. Lalwani GA,Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascularage-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009; 148(1):43-58.e1. 6. Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG.A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-relatedmacular degeneration. Ophthalmology. 2009;116(9):1731-1739. 7. Holz FG, Amoaku W, Donate J,et al; SUSTAIN Study Group. Safety and efficacy of a flexible dosing regimen of ranibizumab in neo-vascular age-related macular degeneration: the SUSTAIN study. Ophthalmology. 2011;118(4):663-671. 8. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ.Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med.2011;364(20):1897-1908. 9. Singer M, Wong P, Wang P-W, Scott L. HORIZON extensiontrial of ranibizumab (LUCENTIS®) for neovascular age-related macular degeneration (AMD):two-year safety and efficacy results. Invest Ophthalmol Vis Sci. 2009;50:E-Abstract 3093.10. Dadgostar H, Ventura AA, Chung JY, Sharma S, Kaiser PK. Evaluation of injection frequency andvisual acuity outcomes for ranibizumab monotherapy in exudative age-related macular degeneration.Ophthalmology. 2009;116(9):1740-1747. 11.Gragoudas ES, Adamis AP, Cunningham ET Jr, FeinsodM, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib forneovascular age-related macular degeneration.N Engl J Med. 2004;351(27):2805-2816. 12. FribergTR, Tolentino M; LEVEL Study Group. Pegaptanib sodium as maintenance therapy in neovascularage-related macular degeneration: the LEVEL study. Br J Ophthalmol. 2010; 94(12):1611-1617.13. Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD. A treat and extend regimenusing ranibizumab for neovascular age-related macular degeneration clinical and economic impact.Ophthalmology. 2010;117(11):2134-2140. 14. Dyer DS. Pegaptanib maintenance in neovascularage-related macular degeneration (NV-AMD) following induction therapy: results of a retrospectivecase series. Invest Ophthalmol Vis Sci. 2009;50:E-Abstract 1914. 15. Curtis LH, Hammill BG, Schul-man KA, Cousins SW. Risks of mortality, myocardial infarction, bleeding, and stroke associated withtherapies for age-related macular degeneration. Arch Ophthalmol. 2010;128(10):1273-1279.16. Matsuyama K, Ogata E, Matsuoka M, Wada M, Takahashi K, Nishimura T. Plasma levels of vas-cular endothelial growth factor and pigment epithelium-derived growth factor before and after intrav-itreal injection of bevacizumab.Br J Ophthalmol. 2010;94(9):1215-1218. 17.Boyer DS. RISE, RIDE:Ranibizumab bested sham injection in diabetic macular edema. Paper presented at: 71st ScientificSessions of the American Diabetes Association; June 24-28, 2011; San Diego, CA. 18. DiabeticRetinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, et al. Randomized trial eval-uating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabeticmacular edema.Ophthalmology. 2010;117(6):1064-1077.e35. 19.Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE Study Group. The RESTORE study: ranibizumab monotherapy or combinedwith laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615-625. 20. Phase 3 study showed MACUGEN® improved vision over standard of care in patientswith diabetic macular edema [press release]. New York, NY: Pfizer Inc; June 5, 2010.http://media.pfizer.com/files/news/press_releases/2010/pfizer_macugen_dme_060510.pdf.Accessed June 3, 2011. 21.Scott IU, Ip MS, VanVeldhuisen PC, et al; SCORE Study Research Group.A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard careto treat vision loss associated with macular edema secondary to branch retinal vein occlusion: theStandard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6.Arch Ophthalmol.2009;127(9):1115-1128. 22. Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group.A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observationto treat vision loss associated with macular edema secondary to central retinal vein occlusion: theStandard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5.Arch Ophthalmol.2009;127(9):1101-1114. 23. Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA StudyGroup. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients withmacular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-1146.e3.24.Wroblewski JJ, Wells JA 3rd, Adamis AP, et al; Pegaptanib in Central Retinal Vein Occlusion StudyGroup. Pegaptanib sodium for macular edema secondary to central retinal vein occlusion.Arch Oph-thalmol. 2009;127(4):374-380. 25. Campochiaro PA, Heier JS, Feiner L, et al; BRAVO Investigators.Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary endpoint results of a phase III study. Ophthalmology. 2010;117(6):1102-1112.e1. 26. Brown DM,Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular edema followingcentral retinal vein occlusion: six-month primary end point results of a phase III study.Ophthalmology.2010;117(6):1124-1133.e1. 27. McIntosh RL, Rogers SL, Lim L, et al. Natural history of centralretinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2010;117(6):1113-1123.e15. 28. Chang LK, Spaide RF, Klancnik JM, et al. Longer-term outcomes from aprospective study of intraviteal ranibizumab as a treatment for decreased visual acuity secondaryto central retinal vein occlusion. Retina. 2011;31(5):821-828. 29. Rogers SL, McIntosh RL, Lim L,et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review.Ophthalmology. 2010;117(6):1094-1101.e5. 30. Diabetic Retinopathy Clinical Research Network,Scott IU, Edwards AR, Beck RW, et al. A phase II randomized clinical trial of intravitreal bevacizumabfor diabetic macular edema. Ophthalmology. 2007;114(10):1860-1867.

To receive AMA PRA Category 1 Credit™, you must complete this Evaluation form and the Post Test. Record your answers to the Post Test in the Answer Box located below. Mail or Fax thiscompleted page to The New York Eye and Ear Infirmary–ICME, 310 East 14th Street, New York, NY 10003 (Fax: 212-353-5703). Your comments help us to determine the extent to which thiseducational activity has met its stated objectives, assess future educational needs, and create timely and pertinent future activities. Please provide all the requested information below. Thisensures that your certificate is filled out correctly and is mailed to the proper address. It also enables us to contact you about future CME activities. Please print clearly or type. Illegiblesubmissions cannot be processed.

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� Yes � No Did you perceive any commercial bias in any part of this activity? IMPORTANT! If you answered “Yes,” we urge you to be specific about where the bias occurredso we can address the perceived bias with the contributor and/or in the subject matter in future activities.

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Circle the number that best reflects your opinion on the degree to which the following learning objectives were met:5 = Strongly Agree 4 = Agree 3 = Neutral 2 = Disagree 1 = Strongly DisagreeAfter successfully completing this activity, I have improved my ability to:

• Discuss alternate treatment protocols for patients with AMD in whom long-term anti-VEGF therapy poses a safety concern 5 4 3 2 1

• Review the current and emerging treatment options for DME and RVO 5 4 3 2 1

• Choose optimal dosing strategies from the available therapies for patients with AMD, DME, or RVO 5 4 3 2 1

1. Please list one or more things, if any, you learned from participating in this educational activity that you did not already know.

____________________________________________________________________________________________________________________________________________

2. As a result of the knowledge gained in this educational activity, what changes, if any, do you plan to make in your practice?

____________________________________________________________________________________________________________________________________________

3. Related to what you learned in this activity, what barriers to implementing these changes or achieving better patient outcomes do you face?

____________________________________________________________________________________________________________________________________________

4. Please check the Core Competencies (as defined by the Accreditation Council for Graduate Medical Education) that were enhanced for you through participation in this activity.

� Patient Care � Practice-Based Learning and Improvement � Professionalism

� Medical Knowledge � Interpersonal and Communication Skills � Systems-Based Practice

5. What other topics would you like to see covered in future CME programs?

____________________________________________________________________________________________________________________________________________

Additional Comments

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Post Test Answer Box

Activity Evaluation/Credit Request

AMD, DME, and RVOCurrent and Emerging Considerations in the Management of

Original Release: September 28, 2011Last Review: September 19, 2011Expiration: September 30, 2012

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AMD, DME, and RVO

Current and Emerging Considerationsin the Management of

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